© American College of Medical Genetics and Genomics
Original Research Article
Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo–Bartter/Gitelman syndrome based on clinical characteristics Natsuki Matsunoshita, MD1, Kandai Nozu, MD, PhD1, Akemi Shono, PhD1, Yoshimi Nozu, MNS1, Xue Jun Fu, MD, PhD1, Naoya Morisada, MD, PhD1, Naohiro Kamiyoshi, MD1, Hiromi Ohtsubo, MD1, Takeshi Ninchoji, MD, PhD1, Shogo Minamikawa, MD1, Tomohiko Yamamura, MD1, Koichi Nakanishi, MD, PhD2, Norishige Yoshikawa, MD, PhD2, Yuko Shima, MD, PhD2, Hiroshi Kaito, MD, PhD1 and Kazumoto Iijima, MD, PhD1 Purpose: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/ GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. Methods: A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. Results: Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass
INTRODUCTION Bartter syndrome (BS) (OMIM #s: type I, 601678; type II, 241200; type III, 607364; type IV, 602522; type IVb, 613090) and Gitelman syndrome (GS) (OMIM # 263800) are inherited autosomal-recessive, salt-losing tubulopathies characterized by hypokalemic metabolic alkalosis. BS and GS are reportedly caused by mutations in genes encoding ion transporters or channels, leading directly or indirectly to loss of function.1–6 These genes include SLC12A1, which encodes the apical furosemide-sensitive Na–K–2Cl cotransporter2; KCNJ1, which encodes the apical renal outer medullary potassium channel3; CLCNKB, which encodes the basolateral chloride channel Kb (expressed in the thick ascending limb of Henle’s loop and in the distal convoluted tubule)1,7; and BSND, which encodes barttin, a subunit of chloride channels Ka and Kb. Mutations in these genes lead to types I–IV BS, respectively.6,8 Combined mutations in both CLCNKA and CLCNKB result in type IVb BS.9,10 By contrast, mutations in the SLC12A3 gene, which encodes the apical thiazide-sensitive Na–Cl cotransporter (NCCT) in
index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease. Conclusions: This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions. Genet Med advance online publication 16 April 2015 Key Words: Bartter syndrome; Gitelman syndrome; pseudo- Bartter; pseudo-Gitelman; salt-losing tubulopathy
the distal convoluted tubule, are responsible for GS.4 Types I, II, IV, and IVb BS (antenatal BS) usually present during the neonatal period with relatively severe symptoms, whereas type III BS (classic BS) presents during early childhood with milder symptoms. In contrast to BS, GS is usually diagnosed during late childhood or adulthood. However, phenotypic overlap frequently occurs between type III BS and GS, which are difficult to diagnose based on their clinical presentations and require genetic tests. For example, some patients with type III BS may show clinical features of GS, including hypomagnesemia and hypocalciuria, and diuretic tests may fail to differentiate between disease-related them.7,11–13 Moreover, mutations in known genes have not been identified in some patients with clinically diagnosed BS/GS. This suggests that some acquired conditions may cause a BS/GS-like disorder, or pseudo-BS/GS (p-BS/GS), associated with loss of sodium or chloride in the urine, stool, or vomitus or with chloride-intake deficiency, resulting in clinical symptoms identical to those of BS/GS. As previously reported, p-BS/GS may be caused by a wide variety of conditions such
1 Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; 2Department of Pediatrics, Wakayama Medical University, Wakayama, Japan. Correspondence: Kandai Nozu (
[email protected])
Submitted 1 November 2014; accepted 17 March 2015; advance online publication 16 April 2015. doi:10.1038/gim.2015.56 Genetics in medicine
1
Original Research Article as surreptitious diuretic use, laxative abuse, a chronic chloridedeficient diet, cyclic vomiting, congenital chloride diarrhea, and cystic fibrosis.5 Despite the need for accurate diagnosis of these three diseases, the differences in their clinical characteristics have rarely been analyzed, and few useful indicators currently exist. This study aimed to clarify the clinical differences among patients with genetically defined type III BS, GS, and p-BS/GS.
MATERIALS AND METHODS
MATSUNOSHITA et al | Pseudo–Bartter and Gitelman syndromes
Statistical analyses
Data are expressed as mean ± SD. All analyses were performed using standard statistical software (JMP version 10 for Windows; SAS Institute, Cary, NC). The clinical backgrounds of the patients were compared using the Mann–Whitney U-, Kruskal–Wallis, Steel–Dwass, Fisher’s exact, Pearson’s χ2, and Student’s t-tests, as appropriate. A P value
